This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our research program integrates functional studies with extensive structural analysis of pattern recognition receptors (PRRs) in complex with their ligands as well as downstream adapters and effector molecules. Both membrane-bound (such as the Toll-like receptors) and cytoplasmic (such as the CATERPILLAR family members and RIG-I/MDA5 antiviral proteins) PRRs are targeted. A critical feature of these innate immune receptors is that they distinguish among various classes of pathogen-specific molecules while retaining responsiveness to a large number of related molecules within a given biochemical class. Understanding such "broad" reactivity at the atomic level is one of the primary goals of the program. Ligand binding by the PRRs not only initiates intracellular signaling cascades leading to innate immune responses against infections, but also allows the innate immune system to orchestrate and potentiate the activities of the adaptive immune system. Our research aims to decipher this signaling network by studying structures of macromolecular complexes using x-ray crystallography.